Biology subjects

Sonnenberg, L.

Publications and source records attributed to Sonnenberg, L..

4 recordsLinked to original sources

bioRxiv2023

Loss or Gain of Function? Neuronal Firing Effects of Ion Channel Mutations Depend on Cell Type

Clinically relevant mutations to voltage-gated ion channels, called channelopathies, alter ion channel function, properties of ionic current and neuronal firing. The effects of ion channel mutations are routinely assessed and characterized as loss of function (LOF) or gain of function (GOF) at the level of ionic currents. Emerging personalized medicine approaches based on LOF/GOF characterization have limited therapeutic success. Potential reasons are that the translation from this binary characterization to neuronal firing especially when considering different neuronal cell types is currently not well understood. Here we investigate the impact of neuronal cell type on the firing outcome of ion channel mutations with simulations of a diverse collection of neuron models. We systematically analyzed the effects of changes in ion current properties on firing in different neuronal types. Additionally, we simulated the effects of mutations in the KCNA1 gene encoding the KV1.1 potassium channel subtype associated with episodic ataxia type 1 (EA1). These simulations revealed that the outcome of a given change in ion channel properties on neuronal excitability is cell-type dependent. As a result, cell-type specific effects are vital to a full understanding of the effects of channelopathies on neuronal excitability and present an opportunity to further the efficacy and precision of personalized medicine approaches. Significance StatementAlthough the genetic nature of ion channel mutations as well as their effects on the biophysical properties of an ion channel are routinely assessed experimentally, determination of their role in altering neuronal firing is more difficult. In particular, cell-type dependency of ion channel mutations on firing has been observed experimentally, and should be accounted for. In this context, computational modelling bridges this gap and demonstrates that the cell type in which a mutation occurs is an important determinant in the effects of neuronal firing. As a result, classification of ion channel mutations as loss or gain of function is useful to describe the ionic current but should not be blindly extend to classification at the level of neuronal firing.

neuroscience↗

bioRxiv2021

Predicting the functional effects of voltage-gated potassium channel missense variants with multi-task learning

PurposeVariants in genes encoding voltage-gated potassium channels are associated with a broad spectrum of neurological diseases including epilepsy, ataxia, and intellectual disability. Knowledge of the resulting functional changes, characterized as overall ion channel gain- or loss-of-function, is essential to guide clinical management including precision medicine therapies. However, for an increasing number of variants, little to no experimental data is available. New tools are needed to evaluate variant functional effects. MethodsWe catalogued a comprehensive dataset of 959 functional experiments across 19 voltage-gated potassium channels, leveraging data from 782 unique disease-associated and synthetic variants. We used these data to train a taxonomy-based multi-task learning support vector machine (MTL-SVM), and compared performance to a baseline of standard SVMs. ResultsMTL-SVM maintains channel family structure during model training, improving overall predictive performance (mean balanced accuracy 0.729 {+/-} 0.029, AU-ROC 0.757 {+/-} 0.039) over baseline (mean balanced accuracy 0.645 {+/-} 0.041, AU-ROC 0.710 {+/-} 0.074). We can obtain meaningful predictions even for channels with few known variants (KCNC1, KCNQ5). ConclusionOur model enables functional variant prediction for voltage-gated potassium channels. It may assist in tailoring current and future precision therapies for the increasing number of patients with ion channel disorders.

bioinformatics↗

bioRxiv2021

Dravet variant SCN1AA1783V impairs interneuron firing predominantly by altered channel activation

Dravet syndrome (DS) is a developmental epileptic encephalopathy mainly caused by functional NaV1.1 haploinsufficiency in interneurons (IN). Recently, a new conditional mouse model expressing the recurrent human p.A1783V missense variant has become available. Here we provide an electrophysiological characterization of this variant in tsA201 cells, revealing both altered voltage-dependence of activation and slow inactivation without reduced sodium peak current density. Simulating IN excitability in a Hodgkin-Huxley one-compartment model suggested surprisingly similar firing deficits for Scn1aA1783V and full haploinsufficiency as caused by heterozygous truncation variants. Impaired NaVA1783V channel activation was predicted to have a significantly larger impact on channel function than altered slow inactivation and is therefore proposed as the main mechanism underlying IN dysfunction. The computational model was validated in cortical organotypic slice cultures derived from conditional Scn1aA1783V mice. Pan-neuronal activation of the p.A1783V variant in vitro confirmed the predicted IN firing deficit while demonstrating normal excitability of pyramidal neurons. Taken together these data demonstrate that despite maintained physiological peak currents density LOF gating properties may match effects of full haploinsufficiency on neuronal level, thereby causing DS. HighlightsNaV1.1A1783V alters voltage-dependence of activation and slow inactivation while not affecting fast inactivation. Depolarizing and hyperpolarizing shifts of activation and slow inactivation curves result in combined channel loss of function (LOF). Simulations of NaV1.1A1783V interneuronal properties indicate reduced action potential firing rates comparable to full SCN1A haploinsufficiency, which is often found in Dravet syndrome. In silico modelling identifies impaired channel activation as the predominant mechanism of channel LOF. Panneuronal induction of Scn1a+/A1783V in a cortical slice culture model confirms restriction of loss of function and its restriction to interneurons.

neuroscience↗

bioRxiv2017

Spatial vision by macaque midbrain

Visual brain areas exhibit tuning characteristics that are well suited for image statistics present in our natural environment. However, visual sensation is an active process, and if there are any brain areas that ought to be particularly 'in tune' with natural scene statistics, it would be sensory-motor areas critical for guiding behavior. Here we found that the primate superior colliculus, a structure instrumental for rapid visual exploration with saccades, detects low spatial frequencies, which are the most prevalent in natural scenes, much more rapidly than high spatial frequencies. Importantly, this accelerated detection happens independently of whether a neuron is more or less sensitive to low spatial frequencies to begin with. At the population level, the superior colliculus additionally over-represents low spatial frequencies in neural response sensitivity, even at near-foveal eccentricities. Thus, the superior colliculus possesses both temporal and response gain mechanisms for efficient gaze realignment in low-spatial-frequency dominated natural environments.

neuroscience↗